Calcium is an essential nutrient; it is a major component of mineralized tissues and is required for normal growth and development of the skeleton and teeth. Over the last decade calcium has enjoyed increased attention due to its potential role in the prevention of osteoporosis. Osteoporosis affects more than 25 million people in the United States and is the major underlying cause of bone fractures in postmenopausal women and the elderly. "Optimal Calcium Intake", JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 272(24): 1942-1948 (1994).
As used herein "osteoporosis" refers to a reduction in the amount of bone mass. Two important factors influencing the occurrence of osteoporosis are optimal peak bone mass attained in the first two to three decades of life and the rate at which bone mass is lost in later years. Adequate calcium intake is critical to achieving optimal peak bone mass and modifies the rate of bone mass loss associated with aging. Wardlaw, "Putting osteoporosis in perspective", JOURNAL OF THE AMERICAN DIETETIC ASSOCIATION, 93(9): 1000-1006 (1993).
Several cofactors modify calcium balance and influence bone mass. These include dietary constituents, hormones, drugs, and the level of physical activity. Unique host characteristics may also modify the effects of dietary calcium on bone health. These include the individual's age and ethnic and genetic background, the presence of gastrointestinal disorders such as malabsorption and the postgastrectomy syndrome, and the presence of liver and renal disease. Interactions among these diverse cofactors may affect calcium balance in either a positive or negative manner and thus alter the optimal levels of calcium intake. "Optimal Calcium Intake", JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 272(24): 1942-1948 (1994).
Calcium requirements vary throughout an individual's lifetime with greater needs occurring during the period of rapid growth in childhood and adolescence, pregnancy and lactation, and in later adult life. Table 1 presents the optimal calcium requirements which were established at a National Institute of Health (NIH) conference on optimal calcium intake held Jun. 6-8, 1994. "Optimal Calcium Intake", JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 272(24): 1942-1948, at 1943 (1994). The participants at the NIH conference considered former Recommended Dietary Allowances (RDA) (10th edition, 1989) for calcium intake as reference levels and used them as guidelines to determine optimal calcium intake in light of new data on calcium-related disorders.
TABLE 1 ______________________________________ OPTIMAL CALCIUM INTAKES OPTIMAL DAILY INTAKE GROUP (in mg of calcium) ______________________________________ Infants Birth-6 months 400 6 months-1 year 600 Children 1-5 years 800 6-10 years 800-1,200 Adolescents/Young Adults 11-24 years 1,200-1,500 Men 25-65 years 1,000 Over 65 years 1,500 Women 25-50 years 1,000 Over 50 years (postmenopausal) On estrogens 1,000 Not on estrogens 1,500 Over 65 1,500 Pregnant and nursing 1,200-1,500 ______________________________________
National consumption data indicate most females over the age of eleven, as well as elderly men, consume amounts of calcium below recommended levels. "Nationwide Food Consumption Survey, Continuing Survey of Food Intakes of Individuals", USDA NFCS, CFS II Report No. 86-3 (1988), pages 62 and 75. According to the Second National Health and Nutrition Examination Survey, the median daily calcium intake for women in the United States was 574 mg. DIETARY INTAKE SOURCE DATA: UNITED STATES, 1976-80, Data From the National Health Survey, Series II, No. 231, DHHS Publication No. (PHS), 83-1681 (1983) page 20.
The preferred approach to attaining optimal calcium intake is through dietary sources. Dairy products are the major contributors of dietary calcium because of their high calcium content (e.g. approximately 250-300 mg/8 oz of cow's milk) and frequency of consumption. As used herein the term "milk" is understood to refer to cow's milk, and the term "dairy products" is understood to refer to food products derived from cow's milk. However, many persons, especially women, prefer to limit their intake of dairy products for several reasons: (a) they dislike the taste of milk/milk products; and/or (b) they have a lactose intolerance; and/or (c) they perceive that some dairy products are too high in fat or protein and may lead to weight gain. Other good food sources of calcium include some green vegetables (e.g. broccoli, kale, turnip greens, Chinese cabbage), calcium-set tofu, some legumes, canned fish, seeds and nuts. Breads and cereals, while relatively low in calcium, contribute significantly to calcium intake because of their frequency of consumption. A number of calcium-fortified food products are currently available, including fortified juices, fruit drinks, breads and cereals. Consumption of these foods may be an additional strategy by persons to achieve their optimal calcium intake.
To maximize calcium absorption, food selection decisions should include consideration of information on the bioavailability of the calcium contained in the food. Bioavailability (absorption) of calcium from food depends on the food's total calcium content and the presence of components which enhance or inhibit calcium absorption. Bioavailability of minerals in food has been traditionally tested by the balance method, which estimates absorption from the difference between ingested intake and fecal output. This approach works well for many nutrients where the difference between intake and excretion is large, but is less well suited for an element such as calcium entering the digestive tract with its secretions. A decline in fractional absorption from 30% to 20% could have profound nutritional significance but would be difficult to detect using the balance method. In contrast, isotopic methods estimate absorption directly from the appearance of the ingested tracer in body fluids. Future clinical evaluations of the bioavailability of calcium from the liquid nutritional product of the present invention will use a state-of-the-art isotope tracer method.
Not all calcium salts are created equally. Calcium salts range from 9% elemental calcium in calcium gluconate to 40% calcium in calcium carbonate. Bioavailability depends on solubility. A new calcium delivery system, Calcium Citrate Malate (CCM) claims to be approximately six-times the solubility of either calcium citrate or calcium malate, both of which are themselves substantially more soluble than calcium carbonate. Smith et al., "Calcium Absorption from a New Calcium Delivery System (CCM)" CALCIFIED TISSUE INTERNATIONAL, 41:351-352 (1987) relates an experiment in humans wherein calcium from CCM was absorbed significantly better than from either calcium carbonate or milk. 38.3% vs 29.6% and 29.4% respectively. WO 91/19692 discloses a process for making a metastable calcium citrate malate.
However, the United States Food and Drug Administration (FDA) has advised that, in order for calcium-containing food ingredients in conventional foods or calcium supplement products to be considered eligible to bear the authorized calcium/osteoporosis health claim, they must meet the requirements in .sctn. 101.14, which include that they have been shown to the FDA's satisfaction to be safe and lawful under the applicable safety provisions of the act (56 FR at 60699). Safety and lawfulness can be demonstrated in a number of ways, including through a showing that a food is generally recognized as a safe (GRAS), affirmed as GRAS by the FDA, listed in the food additive regulations, or subject to a prior sanction. Of the 36 or more calcium-containing ingredients identified by the agency as currently in use the FDA advised that only the following 10 compounds had been demonstrated to be safe and lawful for use in a dietary supplement or as a nutrient supplement: calcium carbonate, calcium citrate, calcium glycerophosphate, calcium oxide, calcium pantothenate, calcium phosphate, calcium pyrophosphate, calcium chloride, calcium lactate, and calcium sulfate (56 FR at 60691).
Table 2 summarizes the enhancement and inhibition factors associated with calcium absorption.
TABLE 2 ______________________________________ FACTORS WHICH ENHANCE OR INHIBIT CALCIUM ABSORPTION Inhibitors Enhancers ______________________________________ Older age (&gt;51) Younger age (11-24) Vitamin D deficiency Healthy vitamin D levels Oxalic acid, fiber & phytates Pregnancy & lactation (only if achlorhydria present) Estrogen (natural & replacement therapy) Caffeine Adequate protein intake Presence of other nutrients in Ca.sup.+2 : PO.sub.4 ratio of 1:1 Ca.sup.+2 supplement Excess protein intake &gt; Specific disaccharides: fructose & 2 .times. RDA lactose Specific organic acids: Citric Malic Ascorbic ______________________________________
Calcium absorption is directly affected by an individual's vitamin D status. Vitamin D deficient individuals absorb less calcium than individuals whose vitamin D stores are adequate. Vitamin D metabolites enhance calcium absorption. The major metabolite 1,25-dihydroxyvitamin D, stimulates active transport of calcium in the small intestine and colon. Deficiency of 1,25-dihydroxyvitamin D, caused by inadequate dietary vitamin D, inadequate exposure to sunlight, impaired activation of vitamin D, or acquired resistance to vitamin D, results in reduced calcium absorption. In the absence of 1,25-dihydroxyvitamin D, less than 10 percent of dietary calcium may be absorbed. Vitamin D deficiency is associated with an increased risk of fractures. Elderly patients are at particular risk for vitamin D deficiency because of insufficient vitamin D intake from their diet, impaired renal synthesis of 1,25-dihydroxyvitamin D, and inadequate sunlight exposure, which is normally the major stimulus for endogenous vitamin D synthesis. This is especially evident in homebound or institutionalized individuals. Supplementation of vitamin D intake to provide 600-800 IU/day has been shown to improve calcium balance and reduce fracture risk in these individuals. Sufficient vitamin D intake should be ensured for all individuals, especially the elderly who are at greater risk for development of a deficiency. Sources of vitamin D, besides supplements include sunlight, vitamin D-fortified liquid dairy products, cod liver oil, and fatty fish. Calcium and vitamin D need not be taken together to be effective. Excessive doses of vitamin D may introduce risks such as hypercalciuria and hypercalcemia and should be avoided. Anticonvulsant medications may alter both vitamin D and bone mineral metabolism particularly in certain disorders, in the institutionalized, and in the elderly. Although symptomatic skeletal disease is uncommon in noninstitutionalized settings, optimal calcium intake is advised for persons using anticonvulsants. "Optimal Calcium Intake", JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 272(24): 1942-1948 (1994).
A number of other dietary factors can also affect calcium absorption. Dietary fiber and phytate have been implicated as inhibiting substances. The binding of calcium by dietary fiber increases with increasing pH. The onset of precipitation of calcium phytates occurs in the pH 4-6 range as in achlorhydria. At low gastric pH values (2-3), phytate does not bind calcium and calcium binding by dietary fiber would be weak if at all. Thus, in normal individuals calcium would reach intestinal sites as soluble species. Depending on the concentrations and binding strengths of various food ligands, some of the calcium will be absorbed at the intestinal sites while the remainder becomes bound as insoluble fiber and phytate complexes. Champagne, "Low Gastric Hydrochloric Acid Secretion and Mineral Bioavailability", ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY, 249: 173-184 (1989).
Simple sugars and organic acids also have an effect on bioavailability. Fructose in orange juice and apple juice promoted positive calcium bioavailability from Calcium Citrate Malate (CCM) which is a combination of CaCO.sub.3, citric acid, malic acid: 5:1:1 mol/mol/mol). The lactose in milk forms a soluble compound with calcium. Organic acids such as citric acid, malic acid and ascorbic acid may also play a role in the favorable absorption of calcium from CCM. Mehansho et al., "Calcium Bioavailability and Iron-Calcium Interaction in Orange Juice", JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION, 8(1):61-68 (1989).
In addition, it is known that high protein intakes, specifically of sulfur containing amino acids, increase urinary calcium excretion. Sulfuric acid radicals are believed to decrease renal tubular resorption. However, consumption of high phosphorus foods, such as meat, can diminish this effect. Spencer et al., "Do Protein and Phosphorous Cause Calcium Loss?", JOURNAL OF NUTRITION, 118:657-660 (1988).
For some individuals, calcium supplements may be the preferred way to obtain optimal calcium intake. Although calcium supplements are available in many salts, calcium carbonate is usually recommended because it contains more elemental calcium per gram than any of the other salts. The disintegration and dissolution characteristics of commercial calcium carbonate preparations, which vary widely, may produce important differences in calcium absorption. Other problems with using large amounts of calcium carbonate is that it can lead to constipation and abdominal distention. When problems arise, calcium lactate or calcium citrate are advised. These substitutions for calcium carbonate are also indicated for people with achlorhydria. A popular commercially available calcium supplement is TUMS 500.TM. which is distributed by SmithKline Beecham, Pittsburgh, Pa., U.S.A. and is labeled as providing 500 mg of elemental calcium (from calcium carbonate per tablet). However, the TUMS 500.TM. label does not indicate that this calcium supplement contains any vitamin D.
U.S. Pat. No. 4,786,510 and U.S. Pat. No. 4,992,282 disclose the use of calcium citrate malate in a beverage or dietary supplement fortified with iron, but do not disclose the addition of vitamin D to such a product. WO 92/19251 and WO 92/21355 disclose the use of calcium citrate malate in a low pH beverage, and suggests that vitamin D be added to such a beverage along with oil flavors or weighing oil. However; neither WO 92/19251 or WO 92/21355 disclose any other details about how to incorporate vitamin D.sub.3 into such a beverage.
EP 0 486 425 A2 discloses a liquid oral nutritional formulation which contains carbohydrates, protein, fat, fiber, calcium, and vitamin D, and has a pH of about 3.5 to 3.9. However, this publication teaches that high amounts of micronutrients such as calcium or magnesium may impair the palatability of the product, and should contain the recommended daily allowance of these nutrients in about one liter or product. In an example in the patent publication this product contains only about 570 mg of calcium per liter and about 211 IU of vitamin D per liter. A commercially available product in accordance with this patent publication is distributed by Sandoz Nutrition under the trade name CITRISOURCE.RTM. and is labeled as providing 570 mg of calcium and 210 IU of vitamin D per liter. By way of comparison, prototypes of a beverage according to the present invention contain about 1,408 mg of calcium per liter and about 338 IU of vitamin D.sub.3 per liter.
U.S. Pat. No. 4,737,375 teaches beverage concentrates and beverages having a pH of 2.5 to 6.5, preferably 3.0 to 4.5, which contains calcium. The use of vitamin D.sub.3 in this beverage is not disclosed. This patent does not teach the use of calcium glycerophosphate (which is used in preferred embodiments of the present invention, as a calcium source. The acidulants used in this prior art beverage are chosen from mixtures of citric acid, malic acid and phosphoric acid, and the weight ratio of total acids to calcium is in the range of 4 to 7. The calcium level is 0.06% to 0.15%, preferably 0.10% to 0.15% of the beverage, by weight. By way of comparison, prototypes of the beverage of the present invention have a weight ratio of total acids to calcium of about 5.1.
Two commercially available beverages which are labeled as being protected by U.S. Pat. No. 7,737,375 are: (1) Sunny Delight.RTM. With Calcium which is distributed by Procter & Gamble, Cincinnati, Ohio 45202 U.S.A.; and (2) HAWAIIAN PUNCH.RTM., DOUBLE C which is distributed by Sundor Brands, Inc., Cincinnati, Ohio 45202 U.S.A.. According to the "Nutrition Facts" on the labels of these commercially available products: (a) either product contains vitamin D; (b) neither product contains any fat; (c) a 240 mL (8 fluid ounce) serving of Sunny Delight.RTM. With Calcium provides 30% of the recommended daily intake of calcium; (d) a 240 mL (8 fluid ounce) serving of HAWAIIAN PUNCH.RTM., DOUBLE C provides 15% of the recommended daily intake of calcium; and (e) and a 240 mL (8 fluid ounce) serving of each of these products provides 100% of the recommended daily intake of vitamin C. Per the product labels, these percent daily values are based on a 2,000 calorie diet. A review of the ingredient listings on the labels of each of these products indicates that both of these beverages are aqueous solutions, and that neither product contains gum arabic. Samples of each of these products were tested regarding their pH values: the pH value of the HAWAIIAN PUNCH.RTM. DOUBLE C was 3.91; and the pH value of the Sunny Delight.RTM. With Calcium was 4.05.
GB 2 196 253 A discloses a beverage containing calcium and vitamin D. A water soluble non-toxic calcium salt is used in a quantity sufficient to provide in the final beverage a calcium ion content of from 1.0.times.10.sup.-2 to 40.times.10.sup.-2 % w/w. The beverage may contain up to 5.times.10.sup.-6 w/w of vitamin D. However, this published patent application does not teach the use of a gum, such as gum arabic or gum tragacanth, in such a beverage to improve vitamin D.sub.3 stability.
The NIH Consensus Statement recommended that the private sector play an active role in promoting optimal calcium intake by developing and marketing a wide variety of calcium-rich foods to meet the needs and tastes of a multiethnic population. "Optimal Calcium Intake", JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 272(24): 1942-1948 (1994). Hence, there is provided in accordance with one aspect of the present invention a low pH beverage fortified with calcium and vitamin D.sub.3. There is provided in accordance with another aspect of the invention a liquid beverage concentrate fortified with calcium and vitamin D.sub.3. There is provided in accordance with yet another aspect of the invention a liquid beverage additive fortified with calcium and vitamin D.sub.3.